C-reactive protein (CRP) is a major acute phase reactant, which is produced primarily in the liver in response to infection, inflammation and trauma (1). CRP has been shown to bind to nuclear autoantigens (2). The primary stimulus for CRP production is IL-6 (3). Serum levels of CRP in disease usually correlate with levels of IL-6 in the blood. In SLE, CRP levels do not correlate with serum IL-6 suggesting an abnormal CRP response in patients with SLE (4).
Extensive efforts to discover the single “function” of CRP have instead demonstrated that CRP exhibits different biological activities under different conditions (1, 3). These activities depend on ligand recognition, activation of complement and interactions with Fc gamma receptors (FcγR) I and II and perhaps FcγRIII. Although CRP may enhance inflammation and ligand clearance through complement activation, one of its most important functions appears to be the direct modulation of inflammation through interaction with FcγR (5). Depending on the level and type of FcγR expressed on cells at the site of CRP interaction, the outcome of CRP binding may be either pro- or anti-inflammatory. Under most conditions it is likely that CRP plays an anti-inflammatory and immunomodulatory role in acute inflammation and helps to clear damaged self and foreign materials from the circulation in a non-inflammatory and non-immunogenic manner.
CRP modulates inflammation in a variety of animal models. Heuertz et al first demonstrated that CRP protects rabbits and mice from C5a induced alveolitis (6, 7). CRP also protects mice from lethality due to lipopolysaccharide (LPS) (8). The ability of CRP to protect mice from LPS was subsequently determined to require FcγR (9). These are acute inflammatory models associated with complement activation and neutrophilic infiltration. However, CRP was also protective in a mouse model of experimental allergic encephalitis (10), a T cell-mediated autoimmune disease.
CRP interacts with nuclear antigens including chromatin and small nuclear ribonuclear protein particles (snRNPs) (reviewed in (2)). In addition, CRP binds to apoptotic cells leading to enhanced phagocytosis and an increase in anti-inflammatory cytokines (11, 12). CRP also influences the course of autoimmune disease in (NZB×NZW)F1 female mice (NZB/W) (13). This effect was attributed to decreased antigenic stimulation and enhanced clearance of nuclear antigens. The protection from nephritis in NZB/W mice was recently confirmed in a transgenic mouse expressing human CRP (14). More recently, the present inventors determined that a single injection of CRP provides long-lasting protection from lupus nephritis and reverses ongoing nephritis in NZB/W mice (15). Interestingly, there was no reduction of autoantibodies to nuclear antigens in CRP-treated mice in either of these studies. CRP was also protective in nephrotoxic nephritis (NTN), an immune complex (IC) nephritis model that does not involve autoantibodies (15). As renal disease was markedly decreased in CRP-treated mice without a corresponding decrease in glomerular IgG or C3 deposition, it appears that CRP can reduce the inflammatory response to IC.
Systemic lupus erythematosus (SLE) is a systemic immune complex disease of humans that affects multiple organ systems. The disease is characterized by rashes, arthritis, lung disease, and kidney disease. It occurs mostly in women and usually strikes during young adulthood. Perhaps the most severely affected organ is the kidney, and glomerulonephritis is the major cause of morbidity and mortality in patients with SLE. The current standard treatment for lupus nephritis is the alkylating agent cyclophosphamide, a strong immunosuppressive drug. Although treatment is generally effective, the drug has many side effects including infections, sterility, hair loss, and malignancy.
A wide variety of agents have been used to treat SLE. These agents may act either by interfering with collaborations between B and T lymphocytes, directly eliminating effector cells, or by blocking individual cytokines. Biological agents have had various levels of success in treating animal models of SLE. However, most agents require repeated treatment with high concentrations of monoclonal antibody or protein antagonists.
The most commonly studied animal model of human SLE is the NZB/W female mouse. This mouse model has many features in common with the human disease including severe proliferative glomerulonephritis, which is the major cause of death in the mice. The mice have high levels of circulating immune complexes (IC), which interact with FcγR in the kidney to induce nephritis. A second mouse model of human SLE is the MRL-Faslpr mouse (MRL/lpr), which exhibits a more rapid progression of disease than the NZB/W mouse.
The innate immune system plays an important role in autoimmunity. One way in which the innate immune system molecules may affect autoimmunity is through the recognition and clearance of autoantigens released from apoptotic or necrotic cells. Other possible mechanisms for protecting against autoimmune-mediated inflammation include altering the cytokine response to inflammatory stimuli and redirecting the adaptive immune system.
CRP is the prototypic acute phase reactant in man and a component of the innate immune system. CRP binds to nuclear antigens that are the targets of the autoantibodies of patients with SLE as well as to damaged membranes and microbial antigens. CRP activates the classical complement pathway and interacts with phagocytic cells through FcγR. CRP is protective against various inflammatory states including endotoxin shock and inflammatory alveolitis. CRP protection against endotoxin shock requires FcγR and is associated with FcγR-dependent induction of interleukin-10 (IL-10) synthesis by macrophages.
It has been reported that CRP is protective against the accelerated disease in NZB/W mice injected with chromatin. It has also been demonstrated that NZB/W mice transgenic for human CRP had a delayed onset of proteinuria and enhanced survival. The ability of CRP to prolong survival in NZB/W mice has been attributed to increased binding and clearance of autoantigens or immune complexes. However, the ability of CRP to regulate acute inflammation suggests an alternative mechanism for its beneficial effects in SLE.
Immune thrombocytopenic purpura (ITP) is an autoimmune disease characterized by platelet clearance mediated by pathogenic platelet-specific antibodies. Current therapies for ITP include untargeted immunosuppression, splenectomy and high dose intravenous immunoglobulin (IVIG). Approaches that harness the immune system's natural regulatory pathways may be promising alternatives with fewer side effects.
IVIG has been used to treat both ITP and lupus nephritis. Siragam et al. have recently described an adoptive transfer model of IVIG treatment of ITP (3). They had previously shown that IVIG ameliorates thrombocytopenia in this model. They have now determined that spleen cells, and specifically, dendritic cells (DC), treated with IVIG in vitro act through FcγR to transfer suppression to mice treated to induce ITP. Although IVIG is an effective treatment for ITP, and to a lesser degree, SLE, it has several limitations. It must be used in very high doses in vivo and it is expensive. It may occasionally exacerbate disease, either due to aggregates or interaction with FcγRIII.